Noise-induced hearing loss (NIHL) and age-related hearing loss (AHL) are two major hearing impairments, and affected individuals often show compromised ability in processing fine temporal structures of sound. While most studies of NIHL and AHL focus on the peripheral defects, much less is known about accompanying alterations in the central auditory system. This proposal will explore the changes of synaptic transmission and the underlying cellular mechanisms following NIHL and AHL at the endbulb of Held synapses. These synapses are the first synaptic connection of the central auditory system and are well known to be important in fine temporal processing. Preliminary data shows that synaptic transmission at mouse endbulbs of Held is compromised with NIHL and AHL, likely due to impaired calcium homeostasis in the endbulb terminals. The first aim of this proposal will test the hypothesis that elevation of calcium concentration at the presynaptic terminal underlines the aberrant synaptic release during sustained activity following NIHL. Synaptic transmission will be evaluated in both normal and NIHL mice utilizing manipulations that modify calcium buffering in the microdomain and nanodomains near the active zone. The source of the calcium elevation will be identified by assessing synaptic transmission while disrupting specific pathways including external calcium influx via voltage-gated calcium channels, Ca-calmodulin dependent calcium channel inactivation, and calcium induced calcium release from internal calcium stores via ryanodine receptors and IP3 receptors. The second aim of this proposal will explore the functional impact of the changes in synaptic transmission following NIHL by examining the firing properties of postsynaptic bushy cells. This aim will test the hypothesis that increase in asynchronous release in NIHL mice leads to decreased synaptic efficacy and compromised temporal precision. Particularly, the study will also explore manipulations that can acutely restore the normal firing properties of bushy cells in slice. The third aim of this proposal will tst the hypothesis that impaired synaptic transmission at the endbulbs during AHL share the same impaired calcium homeostasis mechanisms as observed in NIHL. As in Aims 1 and 2, Aim 3 will examine the synaptic transmission and test the signaling pathways in aged mice with AHL. The long-term goal of this study is to identify the common cellular mechanisms that underlie synaptic modifications of the central auditory system following NIHL and AHL, and to identify manipulations that can acutely rescue normal synaptic function in a preclinical model. Ultimately, these studies could suggest approaches for future clinical treatments of NIHL and AHL.